Neuropeptide Y (NPY) is an endogenous neuropeptide with robust anxiolytic properties. NPY has been implicated in a wide variety of anxiety disorders, including posttraumatic stress disorder (PTSD), and enhancement of NPY levels has been proposed as a potential therapy for PTSD and other anxiety disorders. Low levels of (NPY have been measured in patients with PTSD, and in rodents using the Predator Scent Stress model, which is a model of stress-induced anxiety/PTSD. However, the effect of Predator Scent Stress on NPY release in hippocampus has not yet been demonstrated. Anxiety disorders are considered a maladaptive form of learning, and hippocampal dysfunction has been implicated in anxiety disorders and PTSD. Because of its many clinical implications, it is important to understand how the endogenous release of NPY is regulated. In hippocampus, NPY is released from a subset of inhibitory interneurons that also release GABA. Despite the importance of NPY, very little is known about the physiological properties of the interneurons in hippocampus that release NPY. Experiments in this proposal will investigate the synaptically-evoked spiking properties of NPY-containing interneurons in the CA1 region of hippocampus, including the short-term plasticity of their excitatory inputs from Schaffer collateral (SC) synapses from CA3 and temporoammonic (TA) synapses from entorhinal cortex. Exogenous NPY has been shown to modulate glutamate release at SC synapses onto CA1 pyramidal cells and to decrease the strength of feed-forward inhibition from SC stimulation. It is not known if NPY modulates TA synapses or TA-induced feed-forward inhibition onto CA1 pyramidal cells. We will test the effect of exogenous (bath applied) NPY on the excitation/inhibition ratio and circuit function in CA1 in response to SC and TA stimulation. In addition, the effects on CA1 pyramidal cells of endogenously released NPY will be tested. Finally, we will test for alterations in the release of endogenous NPY in CA1 in a mouse model of anxiety, test for mechanisms underlying the changes, and investigate the effects on CA1 circuit function. These studies will lead to a greater understanding of the regulation of NPY cell spiking and the effects of endogenously released NPY, and may lead to potential therapeutic targets to increase NPY cell spiking and thus raise endogenous levels of NPY.
This project investigates the activation of neurons in hippocampus that release Neuropeptide Y (NPY), which has anxiolytic properties and has been implicated in neuropsychiatric and neurological disorders. It will also determine the effects of NPY on synaptic and circuit function, develop a novel assay for showing effects of endogenously released NPY, and test for alterations in NPY release in an animal model of anxiety. These experiments may lead to new therapeutic targets to increase endogenous NPY levels to treat anxiety disorders.
| Sun, Hua Yu; Li, Qin; Bartley, Aundrea F et al. (2018) Target-cell-specific Short-term Plasticity Reduces the Excitatory Drive onto CA1 Interneurons Relative to Pyramidal Cells During Physiologically-derived Spike Trains. Neuroscience 388:430-447 |
| Li, Qin; Bartley, Aundrea F; Dobrunz, Lynn E (2017) Endogenously Released Neuropeptide Y Suppresses Hippocampal Short-Term Facilitation and Is Impaired by Stress-Induced Anxiety. J Neurosci 37:23-37 |
